Background

Acute heart failure (AHF) is associated with high morbidity and mortality, and represents an unmet medical need because only few therapeutic advances were achieved in the past decades [1]. At least 50% of AHF patients have reduced myocardial contractility.
Studies evaluating inotropic agents to improve this underlying pathophysiological mechanism did not show a benefit. It was demonstrated that inotropic activation causes high rates of arrhythmias, hypotension, myocardial ischemia, and increased mortality, due to the increase of myocardial contraction rate and the shortening of the duration of cardiac systole [2]. Therefore, guidelines recommend the use of inotropic agents only for patients with cardiogenic shock or evidence of marked end-organ hypoperfusion [3,4].
Pre-clinical studies and studies in healthy volunteers and in patients with chronic HF and systolic dysfunction, showed that omecamtiv mecarbil (OM), a selective small molecule activator of cardiac myosin that prolongs myocardial systole without changing the velocity of myocardial contraction, increases stroke volume and cardiac output and decreases heart rate [5-8].
This randomised, double-blind, phase II ATOMIC-AHF study evaluated the pharmacokinetics, the pharmacodynamics, as well as the safety, tolerability, and efficacy of a 48-hour intravenous infusion of 3 doses of OM (targeting mean OM plasma concentrations at 48 hours of 115, 230 and 310 ng/mL) or placebo, in 606 patients with AHF (mean age 66).

Conclusion

In patients with AHF, the intravenous administration of OM did not meet the primary endpoint of dyspnea improvement, but it was generally well tolerated, it increased systolic ejection time, and it may have improved dyspnea in the high-dose group.

Editorial comment [9]

In his editorial, Starling addresses the question of whether OM warrants further development, after the results of the ATOMIC-AHF trial, a well-designed phase II clinical trial that did not meet its primary endpoint: dyspnea. ‘Dyspnea is a complex endpoint and has been shown to be related to markers of volume overload and pulmonary congestion. It is not surprising in this relatively small study that the primary endpoint was not met. Nesiritide failed to reach the primary efficacy endpoint for dyspnea in a similar patient population in a trial of more than 7000 patients. The investigators gambled, as dyspnea is a very challenging endpoint, but is nonetheless very relevant to congested HF patients and necessary to evaluate.’ It is emphasized that there are signals of potential clinical benefit of OM in systolic HF and that unfortunately, it seems that the basic mechanisms responsible for the progression of HF are still poorly understood. ‘OM is a unique pharmacological agent defined as a myosin activator. OM should not be considered as a positive inotropic agent, which tends to decrease SET; indeed, OM increases SET, which may represent a novel and efficacious physiological target for systolic HF. The findings from ATOMIC-[A]HF provide further proof of concept that OM may provide clinical benefit for HF with reduced ejection fraction. For now, caution is advised; more knowledge from the COSMIC-HF trial may clarify the potential role of OM in the treatment of HF.’